The oestrogen paradox

PRACE POGLĄDOWE/REWIEVS
Endokrynologia Polska/Polish Journal of Endocrinology
Tom/Volume 58; Numer/Number 3/2007
ISSN 0423–104X
The oestrogen paradox: a hypothesis
Hipoteza paradoksu estrogenowego
Richard J. Santen
Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, Virginia, USA
Abstract
Epidemiological and observational studies suggest that oestrogens, when used as hormonal therapy in post-menopausal
women, can increase the risk of breast cancer if used long term. However, more recent data suggest that short-term use in
sub-groups of post-menopausal women significantly decreases the risk of breast cancer. This beneficial effect is also observed when high-dose oestrogen is administered to post-menopausal women with breast cancer to cause tumour regression,
a phenomenon which commonly occurs. We consider these divergent responses to oestrogen to represent a “paradox”.
Data from our own and other investigative groups suggest a hypothesis to explain this paradox. Deprivation of oestradiol
in model systems causes cells to adapt and to undergo apoptosis in response to oestrogen. This occurs through the Fas/Fas
ligand death receptor pathway and through alterations in apoptotic mechanisms mediated by mitochondria. This process
of programmed cell death may explain the regression of established breast cancer with oestrogen administration and the
diminution in the rate of new breast cancer diagnoses recently reported. Our hypothesis is based upon pathological data
indicating the presence of a “reservoir” of undiagnosed breast cancer in the population of women who would be starting
on oestrogens as menopausal hormonal therapy. The long-term increased risk of breast cancer may then reflect different
mechanisms. Oestrogens can cause mutations through enhancement of the rate of cell division and concomitantly the
error rate in DNA replication. In addition, oestrogens can be metabolised to directly genotoxic compounds. These carcinogenic processes take much longer, since a number of mutations must accumulate before resulting in breast cancer. These
hypotheses regarding oestrogen-induced apoptosis in the short term and carcinogenesis in the long term now require
rigorous verification but would serve to explain the “oestrogen paradox”.
(Pol J Endocrinol 2007; 58 (3): 222–227)
Key words: oestrogens, breast cancer risk, menopausal hormonal therapy
Streszczenie
Badania epidemiologiczne i obserwacyjne sugerują, że estrogeny stosowane przez długi okres u kobiet w ramach hormonalnej terapii zastępczej, mogą zwiększać ryzyko wystąpienia raka piersi. Jednak ostatnie dane wskazują, że estrogeny
stosowane krótko w podgrupie kobiet w okresie pomenopauzalnym, mogą to ryzyko istotnie zmniejszać. Ten sam korzystny efekt obserwowano również podczas podawania wysokich dawek estrogenów kobietom z rakiem piersi znajdującym się w okresie pomenopauzalnym, powodując regresję guza nowotworowego. Autorzy rozważyli odmienne wzorce
reakcji na podane estrogeny. Zjawisko to można nazwać mianem paradoksu. Dane własne autorów oraz innych zespołów
badawczych sugerują hipotezę, która mogłaby tłumaczyć powyższy „paradoks”. W układzie modelowym deprywacja
wpływu estradiolu powoduje, że komórki adaptują się i rozpoczynają proces apoptozy w odpowiedzi na działanie estrogenów. Zjawisko to przebiega poprzez receptor ścieżki śmierci dla liganda Fas/Fas oraz poprzez modyfikację mechanizmów apoptotycznych pośredniczonych przez mitochondria. Opisany powyżej proces programowanej śmierci komórek
może tłumaczyć zarówno zjawisko regresji istniejącego już raka piersi po podaniu estrogenów, jak również opisywane
ostatnio zmniejszenie częstości wykrywania nowych przypadków raka piersi. Hipoteza ta bazuje na danych wskazujących na istnienie w populacji dużej grupy kobiet, u których rak piersi pozostaje niezdiagnozowany, a które dopiero zaczną
stosować estrogeny w ramach hormonalnej terapii zastępczej w okresie pomenopauzalnym. Obserwowany po dłuższym
czasie wzrost częstości zachorowań na raka piersi u kobiet stosujących estrogeny, musi odzwierciedlać inny mechanizm
działania tych związków. Estrogeny mogą powodować mutacje poprzez wzrost wskaźnika częstości podziałów komórki
Dr. Richard J. Santen
Prof.
Division of Endocrinology Department of Medicine
University of Virginia, Charlottesville
PO Box 800379, Virginia 22908, USA
e-mail: [email protected] 222
Endokrynologia Polska/Polish Journal of Endocrinology 2007; 58 (3)
oraz następczego wzrostu liczby błędów podczas replikacji DNA. Ponadto estrogeny mogą zostać metabolizowane bezpośrednio do związków genotoksycznych. Opisane powyżej procesy karcynogenezy wymagają dłuższego czasu, ponieważ
warunkiem koniecznym dla rozwoju raka piersi jest kumulacja wielu mutacji. Powyższa hipoteza dotycząca indukowanej
apoptozy poprzez podawane w krótkim okresie czasu estrogenów oraz karcynogenezy spowodowanej podawaniem tych
samych związków przez dłuższy czas wymaga ścisłej weryfikacji, jednak stara się wyjaśnić zjawisko „paradoksu estrogenowego”.
(Endokrynol Pol 2007; 58 (3): 222–227)
Introduction
A wide range of epidemiological data suggest that
oestrogens are associated with the development of breast cancer [1]. As shown in Figure 1, bilateral oophorectomy before the age of 35 decreases the risk of breast
cancer. On the other hand, the use of menopausal hormone therapy that includes an oestrogen plus a progestin for more than five years increases the risk. Other
factors known to be associated with an increase in longterm exposure to oestrogens also enhance the chances
that a woman will develop breast cancer. These include early menarche, late menopause, weight gain of more
than 20 kg as an adult, increased bone density and plasma oestrogen levels. A high degree of breast density,
which could reflect tissue oestrogen levels, is also
a major risk factor for breast cancer. Observational data
suggest that long-term oestrogen use increases risk to
as much as 70% in thin women taking oestrogen alone
as MHT for more than 20 years [2].
With these epidemiological and observational data as
a background, it was quite surprising that recently published data suggested that women taking post-menopausal
hormone therapy (MHT) with oestrogen alone for 5–9 years
unexpectedly experienced a decrease in the risk of breast
cancer [3, 4]. However, when the hormone therapy was
taken for more than 20 years the risk appeared to increase
[5, 6]. We call this the “oestrogen paradox,” to highlight the
fact that short-term oestrogen use decreases the risk of breast cancer, whereas long term use increases it. A second
component of the oestrogen paradox is that high-dose
oestrogen therapy in post-menopausal women with breast
cancer causes tumour regression, whereas the anti-oestrogen tamoxifen is equally effective in causing remissions in
similar patient groups [7–9]. It is paradoxical then that both
oestrogens and anti-oestrogens cause tumour regressions.
Short-term oestrogen use and breast
cancer risk
The initial publication of the Women’s Health Initiative (WHI) reported a 23% decrease in invasive breast cancer incidence in patients taking oestrogen alone
compared to placebo, a finding which narrowly missed
statistical significance (HR 0.77; 95% CI 0.59–1.01) [3].
A recent exploratory analysis of updated data from this
Figure 1. Hormonal risk factors associated with an increased risk of breast cancer and related to oestrogen exposure ( for references
supporting the validity of this figure, see Williams RH, Textbook of Endocrinology, 10th Edition [1]
Rycina 1. Hormonalne czynniki ryzyka związane z ekspozycją estrogenową a zwiększone ryzyko wystapienia raka piersi (źródła potwierdzające
zasadność danych przedstawionych w powyższych rycinie patrz: Williams RH, Textbook of Endocrinology, 10th Edycja 10 [1])
223
PRACE POGLĄDOWE
Słowa kluczowe: estrogeny, ryzyko raka piersi, hormonalna terapia zastępcza w okresie pomenopauzalnym
PRACE POGLĄDOWE
The oestrogen paradox: a hypothesis
study examined sub-groups to determine whether
oestrogens might reduce the incidence of breast cancer
significantly in women falling into certain categories [4].
Notably, this analysis reported a statistically significant
33% reduction in invasive breast cancer incidence in
patients who strictly adhered to their oestrogen therapy (HR 0.67, 95% CI 0.47–0.97). In addition, a 31% lower incidence of localised breast cancer (HR 0.69, 95%
CI 0.51–0.95) and a 29% reduction in ductal cancers (HR
0.71, 95% CI 0.52–0.99) were reported in oestrogen users.
The decreases in breast cancer risk were limited to women who had not previously used MHT [4]. In a concurrent report from the Nurses’ Health Study a significant 26% decrease in risk of breast cancer was observed
in obese women and a non-significant 10% decrease in
all study participants taking oestrogen alone for 5–9
years [2]. Other observational studies report a reduction in risk with oestrogen alone but of lesser magnitude and not statistically significant. For example, Schairer et al. [5] reported a 7% reduction in breast cancer
risk at 6 years in women receiving oestrogen alone and
Lyttinen et al. [10] reported a similar 7% reduction. These combined results, while not conclusive, are highly
suggestive of a beneficial effect of oestrogen in reducing breast cancer risk. However, this conclusion must
be considered provisional until confirmation has been
obtained from rigorously conducted additional studies.
Long-term oestrogen use and breast
cancer risk
What are the data regarding the use of oestrogen alone
for more than 20 years? The Nurses’ Health Study also
evaluated women using oestrogen alone for more than
20 years and found a statistically significant 41% increase
in breast cancer risk in women of 50 years of age or older
and a 77% increase in the sub-set of lean women [2].
Earlier studies by Magnusson et al. [11] and Schairer
et al. [5] also reported significantly increased breast
cancer risks in women taking oestrogen alone for more
than 10 years (odds ratio = 2.7) and 16 years (relative risk
= 1.6) respectively. The Million Women study also reported a linear increase in breast cancer risk over time in women receiving MHT with oestrogen alone over a period
of 10 years [6]. In contrast to the other studies reported,
however, the Million Women study found a non-statistically significant increased risk of breast cancer even in
women receiving this therapy for less than 5 years.
High-dose oestrogens as breast
cancer treatment
A second component of the oestrogen paradox is that
women with hormone-dependent breast cancer re-
224
Richard J. Santen
spond to high-dose oestrogens with objective tumour
regressions. This form of therapy was the mainstay of
hormonal treatment of breast cancer from the late 1940s
until the early 1980s [7–9]. When compared in randomised trials to tamoxifen, high-dose oestrogens were
equally efficacious [7] and in one study were associated
with statistically significantly enhanced survival [8] compared to the anti-oestrogen. Extensive studies demonstrated that only specific sub-groups of women respond
to high dose oestrogen [9, 12]. Pre-menopausal women
and those less than one year after the menopause do
not respond at all. Women who had undergone the
menopause many years earlier frequently experienced
objective tumour regressions. The longer the period
after the cessation of menses, the greater is the response rate. Only ER-positive tumours regress in women
receiving high-dose oestrogens [12]. In contrast to high-dose oestrogens, tamoxifen is equally effective in premenopausal and post-menopausal women. We also
consider the fact that women respond in a similar fashion to high-dose oestrogens as to anti-oestrogens to
be an “oestrogen paradox”.
Possible mechanisms to explain
the oestrogen paradox
Our pre-clinical data demonstrate that long-term deprivation of oestradiol causes this sex steroid to trigger cell
death through apoptosis. (Fig. 2A), whereas wild-type
cells with a normal oestrogen milieu exhibit reduced
apoptosis (Fig. 2B) [13–21]. The post-menopausal woman
receiving MHT with oestrogen alone may be considered
to be in a state of long-term oestradiol deprivation. An
extensive review of autopsy studies provides strong evidence that there is a reservoir of undiagnosed breast cancer in post-menopausal women (Table I) [22, 23]. The
short-term reduction in breast cancer in the patients with
undiagnosed occult breast tumours may be due to oestrogen-induced apoptosis of tumour cells. Similarly, the
effect of oestrogen in inducing tumour regressions in
patients with known breast cancer may reflect a similar
phenomenon. We suggest that the increased risk of breast cancer from the long-term use of oestrogens alone
as MHT may occur through a different mechanism, the
genotoxic effects of oestradiol metabolites [24, 25]. The
next sections of this treatise will review the evidence
for each of these statements.
Occult pre-existing breast cancers
in women
Over the past three decades there have been at least
eight studies assessing the frequency of occult malignant
disease, primarily ductal carcinoma in situ (DCIS),
Endokrynologia Polska/Polish Journal of Endocrinology 2007; 58 (3)
Figure 2. Long-term oestradiol-deprived (LTED) MCF-7 cells respond to oestradiol with an increase in apoptosis (2A), whereas wildtype MCF-7 cells respond to the same dose of oestradiol with a reduction in apoptosis (2B).
Table I
Reservoir of occult breast cancer found at autopsy
Evidence for oestradiol-induced apoptosis
Tabela I
Odsetek ukrytych przypadków raka piersi stwierdzonych
podczas autopsji
Recent in vitro studies from our laboratory have shown
that hormone-dependent breast cancer cells deprived
of oestrogen in the long term undergo adaptive changes which paradoxically cause oestrogen to stimulate
apoptosis [13–15] (Fig. 2A). Whereas wild-type MCF-7
cells respond to oestradiol with a reduction in apoptosis, those deprived of oestrogen in the long term exhibit an increase in programmed cell death. Similarly, Jordan et al. demonstrated that long-term tamoxifen exposure also results in adaptation and development of
oestrogen-induced apoptosis [16–21] (Fig. 3, 4). Apoptotic mechanisms in adapted cells involve up-regulation of
the death receptor as well as mitochondrial pathways.
Specific molecular events include activation of the FAS
death receptor/ Fas-ligand complex, the release of cytochrome C from the mitochondria and down-regulation
of the anti-apoptotic factor N-F-Kappa B [14, 15, 18].
Occult DCIS or invasive breast cancer at autopsy
Author
#patients
%DCIS
%IBC
1962 Ryan
#100
0%
0%
1973 Kramer
#70
4.3%
1.4%
1975 Wellings
#67
4.5
0%
1984 Nielsen
#77
14.3%
1.3%
1985 Alpers
#101
8.9%
0%
1985 Bathal
#207
12.1%
1.4%
1987 Bartow
#221
0%
1.8%
1988 Nielsen
#109
14.7%
0.9%
Total cases
#952
7%
1.1%
Table derived from report of Welch et al. [22] and Ryan [23]
found at autopsy in women with no history of breast
cancer [22] (Table I). The frequency of occult DCIS varied considerably between these studies (range 0–15%),
most likely reflecting methodological differences. Variation aside, approximately 7% of the 952 combined
cases from these studies contained occult DCIS and 1%,
occult invasive breast cancers (IBCs) [22]. On the basis
of these results it is probably reasonable to assume that
5–10% of the women entering the WHI and Nurses’
Health Studies had occult breast cancer when they were
initially enrolled.
Long-term oestradiol deprivation
in the WHI and Nurses’ Health Studies
At the time of enrolment participants in the WHI trial
were 63 years old on average and menopausal for more
than 10 years [3]. Plasma oestradiol levels fall precipitously at menopause from 50–600 pg/mL to levels of 5–
–10 pg/mL. Even though breast tissue levels might not
precisely reflect plasma concentrations, one would still
expect a substantial reduction in breast tissue levels and
adaptation to this reduction. If our hypothesis were
correct, then exposure to oestrogen therapy as MHT
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PRACE POGLĄDOWE
Rycina 2. Długotrwale pozbawione wpływu estradiolu (LTED, Long-term oestradiol-deprived) komórki MCF-7 odpowiadają na estradiol
nasileniem procesów apoptozy (2A), podczas gdy natywne (wild type) komórki MCF-7 odpowiadają na tę samą dawkę estradiolu
redukcją apoptozy (2B).
The oestrogen paradox: a hypothesis
Richard J. Santen
Figure 3. MCF-7 cells treated with tamoxifen in the long term
were implanted as xenografts into nude mice. At growth for
4 weeks, they are exposed to oestradiol as shown by “treatment
begins”. Slide adapted from the data of Jordan VC et al. [16–21]
PRACE POGLĄDOWE
Rycina 3. Komórki MCF-7 wystawione przez długi okres czasu
na działanie tamoksifenu zostały implantowane jako ksenografty
do szczepu myszy. Po 4-tygodniowym okresie wzrostu rozpoczęto
podawanie estradiolu (punkt oznaczony na wykresie mianem
„treatment begins” — początek leczenia). Rycina zaadaptowana
z danych Jordan VC i wsp. [16–21].
Figure 5. Two pathways potentially responsible for oestradiolinduced carcinogenesis
Rycina 5. Dwie patogenetyczne ścieżki potencjalnie odpowiedzialne
za indukowane przez estradiol procesy karcynogenezy
MHT for 5–9 years [2, 4]. This hypothesis would also
explain why women who had received MHT earlier in
the WHI study did not experience a reduction in breast
cancer risk [4].
Long term exposure to oestradiol
Figure 4. MCF-7 cells were exposed to tamoxifen long term and
then implanted into nude mice as xenografts. After exposure to
oestradiol as in Figure 3 above they were excised and examined
histologically for apoptosis. Data adapted from the data of Jordan
et al. [16–21]
Rycina 4. Komórki MCF-7 wystawione przez długi okres czasu
na działanie tamoksifenu zostały implantowane jako ksenografty
do szczepu myszy. Po okresie ekspozycji na estradiol, jak to zostało
przedstawione na rycinie 3, zostały one wycięte i poddane badaniu
histologicznemu w celu oceny nasilenia apoptozy. Dane
zaadoptowane z VC i wsp. [16–21]
would induce apoptosis and shrink or even eradicate
the occult tumours, which would reduce the detection
of a cancer by mammography or palpation over the next
several years. This scenario could explain the reduction
in breast cancers diagnosed in the WHI and Nurses’
Health Studies in women receiving oestrogen alone as
226
Why would oestrogen increase the risk of breast cancer
when given for more than 20 years? The commonly
accepted explanation for the carcinogenic effect of
oestrogen is that this sex steroid stimulates breast cancer proliferation genes, increases the rate of breast cell
division and thereby enhances the chances for development of mutations [25]. An additional and more controversial mechanism suggests that metabolites of
oestradiol are directly genotoxic [24, 25] (Fig. 5). Recent
studies demonstrate that oestradiol is converted to
4-OH-oestradiol in human breast tissue via the cytochrome p450 1B1 enzyme and is then oxidised to quinone metabolites. These metabolites are highly reactive and covalently bind to adenine and guanine on DNA,
resulting in depurination, error-prone DNA repair and
point mutations [24]. Other recent studies have shown
that 4-OH oestradiol is directly mutagenic in cellular
mutagenesis assays [26–29]. In addition, 4-OH oestradiol can transform oestrogen receptor (ER)-negative
benign breast epithelial cells into serially transplantable carcinomas in immune deficient mice [28]. Finally,
an ER knock-out model of breast cancer forms tumours
in response to increasing doses of exogenous oestradiol in previously castrated animals [24, 30]. These combined observations suggest that directly genotoxic as
well as ER-mediated mechanisms may be responsible
for the long-term carcinogenetic effects of oestradiol
[24]. In time, the pro-carcinogenic effects of oestradiol
would outweigh the pro-apoptotic effects.
Conclusions
Additional studies are needed to confirm our hypothesis regarding the oestrogen paradox. Specifically, more
comprehensive autopsy studies to determine precisely
the magnitude of the reservoir of occult breast cancers
and their precursor lesions are needed The ability of
highly sensitive imaging strategies, such as digital mammography and MRI, should be evaluated in terms of
their ability to detect occult breast cancers in women
initiating MHT. Direct demonstration of oestrogen-induced apoptosis in breast cancers in women will also
be critical.
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